This project is directed at understanding the role of specific enzyme systems in generating and maintaining host immunity. The approach taken involves the creation of mice with discrete defects in host defenses by using homologous recombination of DNA into the host genome to disrupt relevant genes. Lesions have been introduced that correspond to previously identified mutations in humans that incapacitate important host defense systems. This project relies upon a thorough understanding of the molecular and functional organization of the NADPH oxidase system and the mutations which disable it. Further, the dissection of specific phenotypes associated with the defined genotypes may provide insight into the importance of certain functional domains of the genes of the NADPH oxidase and indicate which sites are most informative for further study. We have used the NADPH oxidase system as a paradigm for the creation of mice with a genetic defect similar to one found in humans, chronic granulomatous disease (CGD). Using homologous recombination, we have created mice by which are deficient in the p47phox gene product, a necessary component of the NADPH oxidase complex.